Nivolumab With Trametinib and Dabrafenib, or Encorafenib and Binimetinib in Treating Patients With BRAF Mutated Metastatic or Unresectable Stage III-IV Melanoma

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PRIMARY OBJECTIVE: I. To determine the safety, tolerability, and efficacy (objective response rates by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of nivolumab in combination with dabrafenib and trametinib or encorafenib and binimetinib in patients with BRAF-mutated metastatic melanom...

PRIMARY OBJECTIVE: I. To determine the safety, tolerability, and efficacy (objective response rates by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of nivolumab in combination with dabrafenib and trametinib or encorafenib and binimetinib in patients with BRAF-mutated metastatic melanoma. SECONDARY OBJECTIVES: I. Safety and tolerability of the nivolumab, dabrafenib, and trametinib triplet combination (NDT). II. Safety and tolerability of the nivolumab, binimetinib and encorafenib . III. Efficacy of the combination as measured by the depth and duration of response by RECIST 1.1 and modified RECIST 1.1 (to include intracranial response). IV. Pharmacodynamic evaluation of combination on circulating markers (immune monitoring). V. Pharmacodynamic evaluation of combination on tumor tissues. VI. Progression- free survival and overall survival OUTLINE: Patients are assigned to 1 of 3 arms. ARM A (NDT, CLOSED): Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, dabrafenib orally (PO) twice daily (BID) on days 1-28, and trametinib PO once daily (QD) on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. ARM B (NT, CLOSED TO ACCRUAL): Patients receive nivolumab IV over 30 minutes on day 1 and 15, and trametinib PO QD on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. ARM C (NEB): Patients receive nivolumab IV over 30 minutes on day 1 and 15, encorafenib PO QD on days 1-28, and binimetinib PO BID on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days then every 3 months for up to 3 years.

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